UCL Discovery



Performance of multi-parametric MRI in men at risk of prostate cancer prior to first biopsy: a paired validating cohort study using template prostate mapping biopsies as reference standardMohamed Abd-Alazeez1, Alex Kirkham2, Hashim U. Ahmed1,3, Manit Arya1,7, Eleni Anastasiadis5, Susan C. Charman4, Alex Freeman6, Mark Emberton1,31. Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK 2. Department of Radiology, University College Hospitals NHS Foundation Trust, London, UK3. Division of Surgery and Interventional Science, University College London, London, UK4. Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine 5. Clinical Effectiveness Unit, Royal College of Surgeons of England, London, UK6. Department of Histopathology, University College Hospitals NHS Foundation Trust, London, UK7. Barts Cancer Institute Keywords:Clinically significant disease, multi-parametric MRI, pre-biopsy, prostate cancer, Template prostate mapping, triage test, transrectal ultrasound guided biopsyAddress for correspondenceMohamed Abd-Alazeez67-73 Riding House StreetDivision of Surgery and Interventional ScienceUniversity College London, London, W1W 7EJ, London, UKTel 020 3447 9194Fax 020 3447 9303E-mail: mohamed.azeez.10@ucl.ac.ukAbstractBackground: Multi-parametric MRI (mp-MRI) has the potential to serve as a non-invasive triage test for men at risk of prostate cancer. Our objective was to determine the performance characteristics of multi-parametric MRI (mpMRI) in men at risk prior to first biopsy using 5mm template prostate mapping (TPM) as the reference standard.Methods: One hundred and twenty nine consecutive men with clinical suspicion of prostate cancer that had no prior biopsy, underwent mpMRI (T1/T2-weighted, diffusion-weighting, dynamic-contrast enhancement) followed by TPM. The primary analysis used: a) radiological scores of suspicion of ≥3 attributed from a 5-point ordinal scale, b) a target condition on TPM of any Gleason pattern ≥4 and/or a maximum cancer core length of ≥4mm and c) two sectors of analysis per prostate (right and left prostate halves). Secondary analyses evaluated the impact of: a) changing the mpMRI score threshold to ≥4 and b) varying the target definition for clinical significance. Results: 141/258 (55%) sectors of analysis showed “Any cancer”; 77/258 (30%) had the target histological condition for the purpose of deriving the primary outcome. Median (with range) for age, PSA, gland volume and number of biopsies taken were 62 years (-41-82), 5.8ng/ml (1.2-20), 40ml (16-137) and 41 cores (20-93). For the primary outcome sensitivity, specificity, positive and negative predictive values and area under the receiver operating curve (with 95% CI) were 94% (88-99%), 23% (17-29%), 34% (28-40%), 89% (79-98%) and 0.72 (0.65-0.79), respectively. Conclusion: MpMRI demonstrated encouraging diagnostic performance characteristics in detecting and ruling-out clinically significant prostate cancer in men at risk who were biopsy naive.IntroductionThere are a number of problems with the current prostate cancer diagnostic pathway that relies on serum prostate specific antigen (PSA) and transrectal ultrasound (TRUS) guided biopsy. Over-diagnosis and over-treatment have been a recognized consequence, but missed diagnosis and poor risk stratification also occur PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hyb2RlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

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ADDIN EN.CITE.DATA 1,2. The only widely accepted correction has been to adopt the strategy of increased sampling ADDIN EN.CITE <EndNote><Cite><Author>Taylor</Author><Year>2002</Year><RecNum>127</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>127</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>John A. Taylor</author><author>Gancarczyk, Kevin J.</author><author>Fant, Gregory V.</author><author>McLeod, David G.</author></authors></contributors><titles><title>Increasing the number of core samples taken at prostate needle biopsy enhances the detection of clinically significant prostate cancer</title><secondary-title>Urology</secondary-title></titles><periodical><full-title>Urology</full-title></periodical><pages>841-845</pages><volume>60</volume><number>5</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>3.An alternative strategy is to identify an area or volume of tissue at high probability of being cancer and target this area at biopsy, either exclusively or at a higher sampling density than the rest of the tissue. Multi-parametric MRI (mpMRI) currently holds the most promise for meeting the requirements of an imaging test which may be able to discriminate clinically significant cancer from areas with no cancer or clinically insignificant cancer within the prostate ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2009</Year><RecNum>3</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="2vr9tzr56ptze7ewdv65e9ai0ptwraw9vdxt">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, Hashim U</author><author>Kirkham, Alex</author><author>Arya, Manit</author><author>Illing, Rowland</author><author>Freeman, Alex</author><author>Allen, Clare</author><author>Emberton, Mark</author></authors></contributors><auth-address>Division of Surgical and Interventional Sciences, University College London, UK. hashim.ahmed@ucl.ac.uk</auth-address><titles><title>Is it time to consider a role for MRI before prostate biopsy?</title><secondary-title>Nature reviews. Clinical oncology</secondary-title></titles><pages>197-206</pages><volume>6</volume><number>4</number><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><label>r00758</label><work-type>Review</work-type><urls><related-urls><url> of the studies to date have used transrectal biopsy as a reference test (which is limited in accuracy), targeted biopsies (which prevents systematic interrogation of negative areas) or radical prostatectomy (which introduces a selection bias in that men have to be histologically diagnosed with cancer and then choose surgery rather than radiotherapy or active surveillance). Transperineal template prostate mapping (TPM) biopsies offer a robust reference standard as the sampling frame is fixed at every 5mm of the whole prostate, allow systematic interrogation of the whole prostate, blinded to the imaging, can be applied to most men undergoing the index imaging test and therefore limit the selection bias. Recently, TPM biopsies have been shown to have little to no miss-classification error when compared to whole-mount radical prostatectomy pathology in the detection of lesions 0.5cc or greater in volume with or without the presence of Gleason pattern 4 or greaterPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmF3Zm9yZDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ADDIN EN.CITE.DATA 6. In this study, we aimed to answer the following question: In men with no previous biopsy who present with a clinical suspicion of prostate cancer (based on high PSA, positive family history and/or abnormal digital rectal examination), to what extent can mpMRI detect and rule-out clinically significant prostate cancer using TPM biopsies as the reference standard, in a real practice setting?Patients and methodsResearch ethics committee exemption was granted. In the period 01/01/2007 to 31/01/2011, men with a clinical suspicion of prostate cancer underwent a mpMRI; those with mpMRI scores of 3 or greater were offered a template mapping biopsy. One hundred and twenty-nine consecutive men were eligible for inclusion in this study as they all had an overall MRI score of ≥3 followed by TPM.Exclusion criteria included: a) prior biopsy, b) previous treatment for prostate cancer, c) PSA >20ng/ml (TPM would have been too invasive for such patients where limited TRUS sampling would suffice), d) >12 months between MRI and TPM, e) patients that did not have TPM, and f) patients that had inconclusive TPM where only limited numbers of biopsies were taken. MRIWe aimed to determine the performance of real-practice mpMRI prior to biopsy and therefore did not select cases based on type of MRI scanner used or whether certain radiology reporters were involved. The index test, mpMRI, comprised T2 weighted (T2W), Diffusion-weighted (DW) and Dynamic contrast enhanced (DCE) imaging with either 1.5 Tesla (Siemens Avanto, n=113) or 3.0 Tesla (Phillips Achieva n=16) magnetic field strengths (Table 1). A multi-channel (at least 8) pelvic phased array coil, but no endorectal coil, was used. The detailed scan parameters for the 1.5T machine are shown in Table 1; the slice thickness at 3T was identical, but the in-plane resolution was slightly better. The contrast used was 20ml of Gadoteric Acid 0.5mmol/ml (Dotarem, Guerbet, France) given by an automated injector coincident with the start of the third dynamic sequence. Our practice for the last 8 years has been to use only a pelvic phased array coil rather than an endorectal coil. This is in keeping with a number of other centres which undertake mpMRI for prostate cancer detection ADDIN EN.CITE <EndNote><Cite><Author>Barentsz</Author><Year>2012</Year><RecNum>291</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>291</rec-number><foreign-keys><key app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barentsz, J. O.</author><author>Richenberg, J.</author><author>Clements, R.</author><author>Choyke, P.</author><author>Verma, S.</author><author>Villeirs, G.</author><author>Rouviere, O.</author><author>Logager, V.</author><author>Futterer, J. J.</author><author>European Society of Urogenital, Radiology</author></authors></contributors><auth-address>Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. j.barentsz@rad.umcn.nl</auth-address><titles><title>ESUR prostate MR guidelines 2012</title><secondary-title>Eur Radiol</secondary-title><alt-title>European radiology</alt-title></titles><periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></periodical><alt-periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></alt-periodical><pages>746-57</pages><volume>22</volume><number>4</number><keywords><keyword>Europe</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/*standards</keyword><keyword>Male</keyword><keyword>Medical Oncology/*standards</keyword><keyword>Prostatic Neoplasms/*diagnosis</keyword><keyword>Radiology/*standards</keyword><keyword>Urology/*standards</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1432-1084 (Electronic)&#xD;0938-7994 (Linking)</isbn><accession-num>22322308</accession-num><urls><related-urls><url> radiologists (each one is reporting at least 100 prostate mpMRIs per year) reported all the mpMR images using a score from 1 to 5 as in the recent European Consensus Guidelines ADDIN EN.CITE <EndNote><Cite><Author>Barentsz</Author><Year>2012</Year><RecNum>291</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>291</rec-number><foreign-keys><key app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barentsz, J. O.</author><author>Richenberg, J.</author><author>Clements, R.</author><author>Choyke, P.</author><author>Verma, S.</author><author>Villeirs, G.</author><author>Rouviere, O.</author><author>Logager, V.</author><author>Futterer, J. J.</author><author>European Society of Urogenital, Radiology</author></authors></contributors><auth-address>Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. j.barentsz@rad.umcn.nl</auth-address><titles><title>ESUR prostate MR guidelines 2012</title><secondary-title>Eur Radiol</secondary-title><alt-title>European radiology</alt-title></titles><periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></periodical><alt-periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></alt-periodical><pages>746-57</pages><volume>22</volume><number>4</number><keywords><keyword>Europe</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/*standards</keyword><keyword>Male</keyword><keyword>Medical Oncology/*standards</keyword><keyword>Prostatic Neoplasms/*diagnosis</keyword><keyword>Radiology/*standards</keyword><keyword>Urology/*standards</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1432-1084 (Electronic)&#xD;0938-7994 (Linking)</isbn><accession-num>22322308</accession-num><urls><related-urls><url>, which have recently been validated ADDIN EN.CITE <EndNote><Cite><Author>Portalez</Author><Year>2012</Year><RecNum>2205</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>2205</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">2205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Portalez, D.</author><author>Mozer, P.</author><author>Cornud, F.</author><author>Renard-Penna, R.</author><author>Misrai, V.</author><author>Thoulouzan, M.</author><author>Malavaud, B.</author></authors></contributors><auth-address>Departments of Radiology, Clinique Pasteur, Toulouse, France.</auth-address><titles><title>Validation of the European society of urogenital radiology scoring system for prostate cancer diagnosis on multiparametric magnetic resonance imaging in a cohort of repeat biopsy patients</title><secondary-title>Eur Urol</secondary-title></titles><periodical><full-title>Eur Urol</full-title></periodical><pages>986-96</pages><volume>62</volume><number>6</number><edition>2012/07/24</edition><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1873-7560 (Electronic)&#xD;0302-2838 (Linking)</isbn><accession-num>22819387</accession-num><urls><related-urls><url>(12)00757-9 [pii]&#xD;10.1016/j.eururo.2012.06.044</electronic-resource-num><language>eng</language></record></Cite></EndNote>8: 1= Clinically significant disease is highly unlikely to be present, 2= Clinically significant disease is unlikely to be present, 3= Clinically significant disease is equivocal, 4= Clinically significant disease is likely to be present, 5= Clinically significant disease is highly likely. MRI Images from each patient were reviewed by one radiologist. The index test was conducted in a blinded manner to the reference test as all mpMRI reports were committed to the electronic medical record prior to the biopsy result becoming available. Some reports (n=38) did not contain numerical scoring data and for these, one designated reporter (AK) provided numerical scores based only on the report text and blinded to histology. Whenever a suspected lesion crossed the midline, both prostate halves (right and left) were attributed the same scoring for that lesion. As the role of mpMRI in future may be to triage men and thus select those that could avoid a biopsy, we incorporated the uncertainty score of ‘3’ to confer a positive index test; thus, mpMRI scores of ≥3 were designated positive for the purpose of the primary outcome. The effect of varying this threshold to ≥4 was also evaluated as a secondary outcome. If the mpMRI was positive in an area proven to harbor clinically insignificant disease, according to the definition used, this area was deemed as false positive. BiopsyAll patients underwent TPM biopsies using a 5mm sampling frame under general anesthesia in the method previously described by Barzell ADDIN EN.CITE <EndNote><Cite><Author>Barzell</Author><Year>2007</Year><RecNum>125</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>125</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winston E. Barzell</author><author>Melamed, Myron R.</author></authors></contributors><titles><title>Appropriate patient selection in the focal treatment of prostate cancer: the role of transperineal 3-Dimensional pathologic mapping of the prostate—a 4-year experience</title><secondary-title>Urology</secondary-title></titles><periodical><full-title>Urology</full-title></periodical><pages>27-35</pages><volume>70</volume><number>Suppl 6A</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>9. Urologists doing TPM biopsies were not blinded to MRI results however all 20 zones of the prostate were systematically biopsied. Target conditions: The pathological outputs from the reference test were grouped into a number of definitions of clinical significance, or target conditions, in order to reflect the fact that no universally accepted definition currently exists. These “Target Conditions” are:UCL definition 1: Gleason ≥ 4+3 and/or maximum cancer core length (CCLmax) ≥ 6mmUCL definition 2: Gleason ≥ 3+4 and/or maximum cancer core length (CCLmax) ≥ 4mmGleason score ≥ 4+3Gleason score ≥ 3+4CCLmax ≥ 6mmCCLmax ≥ 4mmThe target histological condition for the purpose of deriving our primary outcome is one that is used in other large-scale multicenter level I evidence validating cohort studies in which mpMRI is being compared to TPM ADDIN EN.CITE <EndNote><Cite><Author>Simmons</Author><Year>2011</Year><RecNum>245</RecNum><DisplayText><style face="superscript">10,11</style></DisplayText><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">245</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Simmons, Lucy</author><author>Ahmed, H. U,</author><author>Moore, C. M,</author><author>Emberton, M.</author></authors></contributors><titles><title>Imaging for Significant Prostate Cancer Risk Evaluation (PICTURE)</title></titles><volume>2013</volume><number>08 July</number><dates><year>2011</year></dates><publisher></publisher><urls><related-urls><url> app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">246</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Emberton, M.</author></authors></contributors><titles><title>PROMIS - Prostate MRI Imaging Study - Evaluation of Multi-Parametric Magnetic Resonance Imaging in the Diagnosis and Characterization of Prostate Cancer</title></titles><volume>2013</volume><number>08 July</number><dates><year>2011</year></dates><publisher></publisher><urls><related-urls><url>. The histological reporting in our institution follows the classic scheme of interpreting the Gleason grading, the one used before the International Society of Urological Pathology 2005 guidelines ADDIN EN.CITE <EndNote><Cite><Author>Epstein</Author><Year>2005</Year><RecNum>134</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>134</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">134</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jonathan I. Epstein</author><author>Allsbrook, William C.</author><author>Amin, Mahul B.</author><author>Egevad, Lars L.</author></authors></contributors><titles><title>The 2005 international society of urological pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma.</title><secondary-title>Am J Surg Pathol</secondary-title></titles><periodical><full-title>Am J Surg Pathol</full-title></periodical><pages>1228-1242</pages><volume>29</volume><number>9</number><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>12. In other words, Gleason scoring was based on the most frequent pattern, and not the highest grade, detected on histological analysis (although the latter was always available for each TPM zone). Further, the cancer core length was reported as the actual amount of cancer seen in each core without counting the intervening areas of benign glands HYPERLINK \l "_ENREF_13" \o "Karram, 2011 #90"PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJyYW08L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 13. Our target condition definitions is based on the only system that has been validated for a parallel sampling strategy and is based on the traditional volume and grade thresholds for individual lesions that are centred on 0.2cc and 0.5cc in combination with dominant and non-dominant Gleason pattern 4 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1lZDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 14.Statistical considerationsAnalysis was done at half prostate level (right and left). This was done via drawing an imaginary sagital line that passes through the patient urethra and divides the prostate in two halves. This resulted in 258 sectors of analysis out of the 129 patients. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and the area under the receiver operating characteristic curve (AUROC) are presented with 95% confidence intervals (95% CI). Confidence intervals were obtained by bootstrapping using 500 bootstrap samples in order to account for the fact that these sectors of analysis were not independent of each other ADDIN EN.CITE <EndNote><Cite><Author>Efron</Author><Year>1993</Year><RecNum>1921</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>1921</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">1921</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Bradley Efron</author><author>Tibshirani, Robert J.</author></authors></contributors><titles><title>An Introduction to the Bootstrap (Chapman &amp; Hall/CRC Monographs on Statistics &amp; Applied Probability)</title></titles><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>15.Our predefined primary objective was to assess the ability of mpMRI (with a score of ≥3/5 considered positive) to detect and rule-out clinically significant disease, defined as any cancer with Gleason pattern 4 or greater (≥3+4) and/or maximum cancer core length (CCLmax ≥4mm]) (UCL definition 2), in one prostate half (right or left).Our predefined secondary objectives were to examine the performance of the index test by a) changing the mpMRI score threshold to ≥4 and b) varying the target histological definition for clinical significance .ResultsBaseline demographic data are presented in Table 2. Primary outcomeIn ruling-out UCL definition 2 clinically significant cancer, mpMRI had a sensitivity and NPV of 94% (95% CI, 88-99%) and 89% (95% CI, 79-98%), respectively (Table 3). In ruling in UCL definition 2 cancer, mpMRI had a specificity and PPV of 23% (95% CI, 17-29%) and 34% (95% CI, 28-40%), respectively.Secondary outcomesThe performance of the test for different levels of clinical significance on TPM at mpMRI threshold of ≥3 is shown in Table 3. The sensitivity for the detection of Gleason 4+3 disease using an mpMRI score of ≥3 was 100%.When using an mpMRI score of ≥4 to rule-out UCL definition 2 cancer, we had lower sensitivity of 68% (95% CI, 56-78%) with reduction in NPV (83% [95% CI, 77-89%]) (this is not a significant decrease). In ruling-in UCL definition 2 cancer at an mpMRI score of ≥4, both specificity (69% [95% CI, 61-76%]) and PPV (48% [95% CI, 38-58%]) improved. The results for other definitions of significance are shown in Table 4.Table 5 shows AUROC curve values for different definitions of clinically significant disease at mpMRI scores 1-5.DiscussionSummary of ResultsThe accuracy of mpMRI at detecting clinically significant prostate cancer varied with the mpMRI threshold that was used to declare a lesion as being present or absent. If the indeterminate score of 3 was included as a positive mpMRI, high sensitivity (93-100%) and NPV (89-100%) were achieved, but with low specificity (19-23%) and PPV (6-34%). When the indeterminate state was omitted and mpMRI scores of 4 and 5 only were used, specificity (61-69%) and PPV (11-48%) improved substantially whilst only marginally compromising sensitivity (68-92%) and NPV (83-99%). The choice of threshold depends on the purpose of the test. Some have argued that the greatest clinical utility for mpMRI is as a triage test to rule-out clinically significant prostate cancer so that men can avoid biopsies or reduce the burden of biopsy in areas that are negative on imaging. For this purpose, the NPV of 89-100% that we have demonstrated (with negative defined as a radiological score of 1 or 2) would add some weight to this argument.The low specificities that we have demonstrated are in part a consequence of applying our definitions of clinical significance on histology rigidly. In other words, even if cancer was found in the mpMRI suspicious area it would be discounted as a false positive if the amount or grade did not meet the pre-specified threshold for clinical significance; others have considered any cancer detected in MRI suspicious areas as true positives regardless of burden of disease found. ADDIN EN.CITE <EndNote><Cite><Author>Puech</Author><Year>2009</Year><RecNum>1</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puech, P.</author><author>Potiron, E.</author><author>Lemaitre, L.</author><author>Leroy, X.</author><author>Haber, G. P.</author><author>Crouzet, S.</author><author>Kamoi, K.</author><author>Villers, A.</author></authors></contributors><auth-address>Department of Radiology, Centre Hospitalier Regional Universitaire de Lille, France.</auth-address><titles><title>Dynamic contrast-enhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens</title><secondary-title>Urology</secondary-title><alt-title>Urology</alt-title></titles><periodical><full-title>Urology</full-title><abbr-1>Urology</abbr-1></periodical><alt-periodical><full-title>Urology</full-title><abbr-1>Urology</abbr-1></alt-periodical><pages>1094-9</pages><volume>74</volume><number>5</number><keywords><keyword>Aged</keyword><keyword>*Contrast Media</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging/methods</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Prostatectomy</keyword><keyword>Prostatic Neoplasms/*pathology/*surgery</keyword></keywords><dates><year>2009</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1527-9995 (Electronic)&#xD;0090-4295 (Linking)</isbn><accession-num>19773038</accession-num><urls><related-urls><url>. 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ADDIN EN.CITE.DATA 17 using T2 and spectroscopy sequences. Other studies using whole-mount prostatectomy as reference standard support the proposition that mpMRI has encouragingly high performance characteristics for detecting and ruling-out clinically significant prostate cancer ADDIN EN.CITE <EndNote><Cite><Author>Turkbey</Author><Year>2011</Year><RecNum>2616</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>2616</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">2616</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turkbey, B.</author><author>Mani, H.</author><author>Shah, V.</author><author>Rastinehad, A. R.</author><author>Bernardo, M.</author><author>Pohida, T.</author><author>Pang, Y.</author><author>Daar, D.</author><author>Benjamin, C.</author><author>McKinney, Y. L.</author><author>Trivedi, H.</author><author>Chua, C.</author><author>Bratslavsky, G.</author><author>Shih, J. H.</author><author>Linehan, W. M.</author><author>Merino, M. J.</author><author>Choyke, P. L.</author><author>Pinto, P. A.</author></authors></contributors><auth-address>Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.</auth-address><titles><title>Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds</title><secondary-title>J Urol</secondary-title></titles><periodical><full-title>J Urol</full-title></periodical><pages>1818-24</pages><volume>186</volume><number>5</number><edition>2011/09/29</edition><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1527-3792 (Electronic)&#xD;0022-5347 (Linking)</isbn><accession-num>21944089</accession-num><urls><related-urls><url>(11)04362-X [pii]&#xD;10.1016/j.juro.2011.07.013</electronic-resource-num><language>eng</language></record></Cite></EndNote>18.Controversy continues on the use of endorectal coils, 3T machines and the relative value of the different components of a ‘multi-parametric’ scan. However, there is increasing evidence that both DW and DCE improve the performance of the test HYPERLINK \l "_ENREF_19" \o "Tanimoto, 2007 #2501"PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5pbW90bzwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

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ADDIN EN.CITE.DATA 19-22. In our institution, we achieved similar results to groups using endorectal coil. According to the recently published ESUR guidelines ADDIN EN.CITE <EndNote><Cite><Author>Barentsz</Author><Year>2012</Year><RecNum>291</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>291</rec-number><foreign-keys><key app="EN" db-id="p9f9e2p9uvdpznezfe4vrts052xrrvrr0drf">291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barentsz, J. O.</author><author>Richenberg, J.</author><author>Clements, R.</author><author>Choyke, P.</author><author>Verma, S.</author><author>Villeirs, G.</author><author>Rouviere, O.</author><author>Logager, V.</author><author>Futterer, J. J.</author><author>European Society of Urogenital, Radiology</author></authors></contributors><auth-address>Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. j.barentsz@rad.umcn.nl</auth-address><titles><title>ESUR prostate MR guidelines 2012</title><secondary-title>Eur Radiol</secondary-title><alt-title>European radiology</alt-title></titles><periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></periodical><alt-periodical><full-title>Eur Radiol</full-title><abbr-1>European radiology</abbr-1></alt-periodical><pages>746-57</pages><volume>22</volume><number>4</number><keywords><keyword>Europe</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/*standards</keyword><keyword>Male</keyword><keyword>Medical Oncology/*standards</keyword><keyword>Prostatic Neoplasms/*diagnosis</keyword><keyword>Radiology/*standards</keyword><keyword>Urology/*standards</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1432-1084 (Electronic)&#xD;0938-7994 (Linking)</isbn><accession-num>22322308</accession-num><urls><related-urls><url>, Barentsz et al. recommended 3 different protocols for detection, staging and for nodes and bone metastases. In the detection protocol they advised with T2W + DW + DCE imaging without an endorectal coil. They added that this can adequately be done at 1.5T using 8-16 channel pelvic phased array.Most studies of MRI in the prostate have divided up the prostate into numerous sectors for analysis. While this has the advantage of increasing the number of data points, and enables the assessment of the performance of MR in different regions, it has fundamental drawbacks: edge effects increase with the number of sectors, and figures for specificity and NPV are not easy to interpret when reapplied to the level of the whole prostate ADDIN EN.CITE <EndNote><Cite><Author>Kirkham</Author><Year>2006</Year><RecNum>312</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>312</rec-number><foreign-keys><key app="EN" db-id="xvf9tsfsn0wracezpr95atsxtp5xa22dfsa9">312</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkham, A.</author><author>Emberton, M.</author><author>Allen, C.</author></authors></contributors><titles><title>How Good is MRI at Detecting and Characterising Cancer within the Prostate?</title><secondary-title>European Urology</secondary-title></titles><periodical><full-title>European Urology</full-title></periodical><pages>1163-1175</pages><volume>50</volume><number>6</number><dates><year>2006</year><pub-dates><date>Dec 1</date></pub-dates></dates><label>p00094</label><urls><pdf-urls><url>. We analysed the prostate in halves rather than wholes because of the high prevalence of disease in our cohort, but did not divide further into sectors, and the results are therefore directly relevant to some important clinical questions ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2012</Year><RecNum>1925</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>1925</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">1925</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, H. U.</author><author>Hindley, R. G.</author><author>Dickinson, L.</author><author>Freeman, A.</author><author>Kirkham, A. P.</author><author>Sahu, M.</author><author>Scott, R.</author><author>Allen, C.</author><author>Van der Meulen, J.</author><author>Emberton, M.</author></authors></contributors><auth-address>Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.</auth-address><titles><title>Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study</title><secondary-title>Lancet Oncol</secondary-title></titles><periodical><full-title>Lancet Oncol</full-title></periodical><pages>622-32</pages><volume>13</volume><number>6</number><edition>2012/04/20</edition><dates><year>2012</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1474-5488 (Electronic)&#xD;1470-2045 (Linking)</isbn><accession-num>22512844</accession-num><urls><related-urls><url>(12)70121-3 [pii]&#xD;10.1016/S1470-2045(12)70121-3</electronic-resource-num><language>eng</language></record></Cite></EndNote>24. 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ADDIN EN.CITE.DATA 25. Further, we accounted for adjacency by conducting boot-strap analyses.Clinical implicationsMost studies have used a dichotomous result to declare whether mpMRI is normal or abnormal. By applying an ordinal 5-point scale we can begin to explore the impact of incorporating indeterminate results within our definition of normal or abnormal. Our observation that the test result is sensitive to the probability threshold used may allow us to use mpMRI in a more intelligent manner than we had previously contemplated. What is the implication of a negative scan of one half of the prostate – in other words, an MRI score of 1-2, which occurred in 18% of prostate halves? In our population, the implication was a very high chance of that half being free of Gleason dominant 4 tumour (none were missed), a 93% chance of being free of any Gleason pattern 4 and a 98% chance that the CCLmax would be <6mm. If both prostate halves are negative, a decision to defer biopsy might seem reasonable if these data are substantiated in larger multicentre studies in which the unit of analysis is the whole prostate. We are currently conducting such a study.In contrast, if a mpMRI is attributed a score of 4 or 5 (Figure 1) then the probability of clinically significant disease will be around 50%, (though for any tumour 73%). Accounting for this apparently low figure are many tumours correctly identified on mpMRI but falling below the thresholds for clinical significance: in practice the level of PPV is useful with encouragingly high positive hit-rates with targeted biopsies using a limited number of cores HYPERLINK \l "_ENREF_26" \o "Haffner, 2011 #264"PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWZmbmVyPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA 26-28.The indeterminate mpMRI remains a problem (Figure 2), though is an under-reported phenomenon HYPERLINK \l "_ENREF_29" \o "Rouse, 2011 #269"PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3VzZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 29. We usually see a score of 3 as a positive signal to biopsy, with the mpMRI findings still useful for targeting the equivocal area. However, if the aim of the scan is to rule-out large volume or high grade (Gleason dominant 4) disease, a score of 3 might prompt deferring the biopsy after a period of surveillance. Such decision-making will depend on a balance of patient factors such as age, comorbidity and competing mortality risk assessment as well as anxiety.Overall, if mpMRI can be used to defer or reduce the burden of biopsy in some patients, and to target suspicious foci in most others, it might serve as a rational triage test ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2009</Year><RecNum>3</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="2vr9tzr56ptze7ewdv65e9ai0ptwraw9vdxt">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, Hashim U</author><author>Kirkham, Alex</author><author>Arya, Manit</author><author>Illing, Rowland</author><author>Freeman, Alex</author><author>Allen, Clare</author><author>Emberton, Mark</author></authors></contributors><auth-address>Division of Surgical and Interventional Sciences, University College London, UK. hashim.ahmed@ucl.ac.uk</auth-address><titles><title>Is it time to consider a role for MRI before prostate biopsy?</title><secondary-title>Nature reviews. Clinical oncology</secondary-title></titles><pages>197-206</pages><volume>6</volume><number>4</number><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><label>r00758</label><work-type>Review</work-type><urls><related-urls><url>. In addition, in the case of a positive diagnosis of tumour, the pre-biopsy mpMRI is immediately available for staging, and is free of post-biopsy artefact, which can reduce its accuracy.Our study had some limitations. The first relates to the nature of our study. We chose to analyze and report our real-life practice experience. We did this as one of the major critiques of mpMRI is that it can only be done within specialist units and rigid protocols. This criticism, if correct, compromises the external validity of some of the studies that have been published to date. Second, our cohort incorporated some work-up bias. Patients with an mpMRI score of 1 or 2 throughout the prostate tended not to choose TPM over TRUS biopsy. We could therefore not include them. Adding more to that is the use of TPM as a reference standard rather than TRUS biopsy. These factors lead to high prevalence of disease in our cohort. Since prevalence was high, one would expect to see a low NPV. However our NPV was 89-100% for different definitions of clinically significant disease. It is also known that the prevalence does not directly affect sensitivity and specificity whereas it affects positive and negative predictive values. Our sensitivity amongst different definitions of clinically significant disease was 93-100%.Third, despite the fact that template biopsies perform well for the detection of significant disease (both in theoretical studies and in practice ADDIN EN.CITE <EndNote><Cite><Author>Bittner</Author><Year>2013</Year><RecNum>26</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="taxa90fps2efw7ea52gxtzsiz0t02xzf0fd2">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bittner, N.</author><author>Merrick, G. S.</author><author>Butler, W. M.</author><author>Bennett, A.</author><author>Galbreath, R. W.</author></authors></contributors><auth-address>Tacoma/Valley Radiation Oncology Centers, Tacoma, WA.</auth-address><titles><title>Incidence And Pathologic Features Of Prostate Cancer Detected On Transperineal Template-Guided Mapping Biopsy Following Negative Transrectal Ultrasound-Guided Biopsy</title><secondary-title>J Urol</secondary-title></titles><edition>2013/02/19</edition><dates><year>2013</year><pub-dates><date>Feb 14</date></pub-dates></dates><isbn>1527-3792 (Electronic)&#xD;0022-5347 (Linking)</isbn><accession-num>23416641</accession-num><urls><related-urls><url>(13)00290-5 [pii]&#xD;10.1016/j.juro.2013.02.021</electronic-resource-num><language>Eng</language></record></Cite></EndNote>30 , with figures of up to 87% for the detection of significant tumour), they are arguably less accurate than radical prostatectomy, and we used a core biopsy technique to estimate tumour significance. Although the technique for doing so has been validated HYPERLINK \l "_ENREF_14" \o "Ahmed, 2011 #247"PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1lZDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 14, it introduces another potential source of error.Finally, although it is widely recognized that not all prostate cancer requires treatment ADDIN EN.CITE <EndNote><Cite><Author>Ahmed</Author><Year>2009</Year><RecNum>336</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>336</rec-number><foreign-keys><key app="EN" db-id="pfar9w2x652pfeevww9papxhxfp5ev9tfwav">336</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmed, H. U.</author></authors></contributors><auth-address>Division of Surgery and Interventional Sciences, University College, and the National Institute for Health Research-Comprehensive Biomedical Research Centre, University College Hospital, London.</auth-address><titles><title>The index lesion and the origin of prostate cancer</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1704-6</pages><volume>361</volume><number>17</number><edition>2009/10/23</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Neoplasm Metastasis/genetics/pathology</keyword><keyword>Prognosis</keyword><keyword>Prostatic Neoplasms/genetics/*pathology/therapy</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct 22</date></pub-dates></dates><isbn>1533-4406 (Electronic)&#xD;0028-4793 (Linking)</isbn><accession-num>19846858</accession-num><urls><related-urls><url> [pii]&#xD;10.1056/NEJMcibr0905562</electronic-resource-num><language>eng</language></record></Cite></EndNote>31, the definitions of clinically significant disease are inevitably contentious. We attempted to include as many as possible to allow for the differences of opinion that currently exist, especially with regard to Gleason 4 disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QbG91c3NhcmQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

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ADDIN EN.CITE.DATA 32,33.ConclusionA normal multi-parametric MRI – that is, one with a score of 1 or 2 - confers a high probability (89-100%) of freedom from clinically significant prostate cancer and as a result, may allow some men to defer or reduce the burden of prostate biopsy. The positive predictive value for clinically significant disease – that is, lesions scoring 4 or 5 on mpMRI – was approximately 50%, something which may allow these patients to benefit from targeted biopsy. AcknowledgementsMohamed Abd-Alazeez receives funding from the Egyptian government. Hashim Uddin Ahmed and Mark Emberton receive funding from the Medical Research Council, the NIHR-HTA, NIHR-i4i, the US NIH/NCI, Pelican Cancer Foundation, Prostate Cancer UK and St Peter’s Trust. This work was part funded by research support for Mark Emberton and Alex Kirkham from the UK National Institute of Health Research UCLH/UCL Comprehensive Biomedical Research Centre, London, UK. Manit Arya would like to acknowledge Orchid (male cancer charity) and Barts and London charity.Conflict of interest:None of the funding sources had any role in the data acquisition, analyses and production of this manuscript. Other sources of fundingMark Emberton and Hashim U Ahmed receive funding from USHIFU and Advanced Medical Diagnostics for clinical trials. Mark Emberton is a paid consultant to Steba Biotech, USHIFU and Sanofi-Aventis. Mark Emberton has received research support by GSK for a study evaluating the role of MRI in men with prostate cancer. Mark Emberton and Hashim Ahmed have previously received medical consultancy fees from GE Healthcare/Oncura and Hashim Ahmed previously from Steba Biotech. Mark Emberton is a medical director of Mediwatch PLC. References ADDIN EN.REFLIST 1.Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V et al. Screening and prostate-cancer mortality in a randomized European study. 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A biopsy simulation study to assess the accuracy of several transrectal ultrasonography (TRUS)-biopsy strategies compared with template prostate mapping biopsies in patients who have undergone radical prostatectomy. BJU Int 2012; 110(6): 812-820.7.Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G et al. ESUR prostate MR guidelines 2012. European radiology 2012; 22(4): 746-757.8.Portalez D, Mozer P, Cornud F, Renard-Penna R, Misrai V, Thoulouzan M et al. Validation of the European society of urogenital radiology scoring system for prostate cancer diagnosis on multiparametric magnetic resonance imaging in a cohort of repeat biopsy patients. Eur Urol 2012; 62(6): 986-996.9.Barzell WE, Melamed MR. Appropriate patient selection in the focal treatment of prostate cancer: the role of transperineal 3-Dimensional pathologic mapping of the prostate—a 4-year experience. Urology 2007; 70(Suppl 6A): 27-35.10.Simmons L, Ahmed HU, Moore CM, Emberton M. 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